Intensity scaling of conventional brain magnetic resonance images avoiding cerebral reference regions: A systematic review

Background Conventional brain magnetic resonance imaging (MRI) produces image intensities that have an arbitrary scale, hampering quantification. Intensity scaling aims to overcome this shortfall. As neurodegenerative and inflammatory disorders may affect all brain compartments, reference regions within the brain may be misleading. Here we summarize approaches for intensity scaling of conventional T1-weighted (w) and T2w brain MRI avoiding reference regions within the brain. Methods Literature was searched in the databases of Scopus, PubMed, and Web of Science. We included only studies that avoided reference regions within the brain for intensity scaling and provided validating evidence, which we divided into four categories: 1) comparative variance reduction, 2) comparative correlation with clinical parameters, 3) relation to quantitative imaging, or 4) relation to histology. Results Of the 3825 studies screened, 24 fulfilled the inclusion criteria. Three studies used scaled T1w images, 2 scaled T2w images, and 21 T1w/T2w-ratio calculation (with double counts). A robust reduction in variance was reported. Twenty studies investigated the relation of scaled intensities to different types of quantitative imaging. Statistically significant correlations with clinical or demographic data were reported in 8 studies. Four studies reporting the relation to histology gave no clear picture of the main signal driver of conventional T1w and T2w MRI sequences. Conclusions T1w/T2w-ratio calculation was applied most often. Variance reduction and correlations with other measures suggest a biologically meaningful signal harmonization. However, there are open methodological questions and uncertainty on its biological underpinning. Validation evidence on other scaling methods is even sparser.


Information sources
6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.

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Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.4 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

Data collection process
9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

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Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

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10b List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information.

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Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

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Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.Tables 3, 4, and 5 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

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13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.
Tables 3, 4, 5, Suppl.File S2 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.Tables 3, 4, 5, Suppl.File S2 13d Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

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13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).NA 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.NA

Section and Topic
Item # Checklist item Location where item is reported

Reporting bias assessment
14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).NA

Certainty assessment
15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.NA

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
5, Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.Figure 1, Suppl.File S2

Study characteristics
17 Cite each included study and present its characteristics.6, Table 2 Risk of bias in studies 18 Present assessments of risk of bias for each included study.Figure 2 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.

Results of syntheses 20a
For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.

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20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.
8-16, Tables 4, 5 20c Present results of all investigations of possible causes of heterogeneity among study results.NA 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.NA Provide registration information for the review, including register name and registration number, or state that the review was not registered.424bIndicatewhere the review protocol can be accessed, or state that a protocol was not prepared.424cDescribe and explain any amendments to information provided at registration or in the protocol.NA Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.
Submission formCompeting 26 Declare any competing interests of review authors.Submission